Lung cancer is the leading cause of all cancer deaths in the U.S. and worldwide. Lung cancer risk and survival are heterogeneously distributed among U.S. populations. African-American men have a higher incidence of and poorer survival from lung cancer than European-American men, even after adjusting for smoking and socioeconomic factors. The tumor-specific biological factors responsible for the racial differences are not yet understood. The goal of this project is to define the mechanisms by which the JAK/STAT3 pathway operates as a key biological contributor of racial health disparities in non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer. Our preliminary data suggest that LUADs from African Americans are more likely than LUADs from European Americans to have JAK/STAT3 pathway mutations that directly induce persistent activation of Signal Transducer and Activator of Transcription-3 (STAT3). STAT3 is an oncogenic transcription factor that is hyperactivated in many cancers. It drives expression of genes that regulate anti-apoptotic responses, angiogenesis, cell proliferation, tumor progression, and therapeutic resistance. The premise of this application is that the JAK/STAT3 signaling axis is inappropriately activated by mutations that are more common in LUAD from African Americans than European Americans, and that therapeutic intervention will be of clinical benefit to a molecular subset of patients with LUAD. Given that the molecular subset is more common in African Americans, research on this topic could help narrow the gap in health disparities. Aim 1 will characterize the molecular profiles in LUAD from African Americans and European Americans focusing on JAK/STAT3 and impact on racial differences. In Aim 2, we will utilize CRISPR-mediated genome editing on patient-derived models of cancer from LUAD tumors from African Americans, and other models, to test the hypothesis that aberrant STAT3 activation results from specific mutations in the JAK/STAT3 pathway, and that the mutations drive LUAD development and tumor progression. In Aim 3, utilizing patient-derived LUAD xenografts primarily from African-American patients, we will test the hypothesis that the JAK/STAT3 pathway mutations we identified can serve as predictive biomarkers for effective antitumor response to STAT3 blockade in LUAD, and we will further clarify novel biomarkers of effective tumor response. At the conclusion of this project, we will have uncovered a novel set of biological determinants of NSCLC health disparities. If the results of the study support our hypothesis, they will provide a path to future clinical trials that may improve the clinical outcome of LUAD patients and help reduce lung cancer health disparities.